Sialic acids are carbohydrates which form a family of about 40 naturally occurring derivatives of neuraminic acid and which all except one are N-acylated (Schauer et al., 1995; Varki, 1992). They are distinguished from another by N and/or O substituents. N substituents are primarily acetyl and glycolyl groups. O substituents are, among others, acetyl, lactoyl, methyl, sulfate and phosphate groups. The most abundant representative of sialic acids is N-acetylneuraminic acid (NeuNAc), which is the precursor of all other sialic acids. Sialic acids are the terminal monosaccharides of complex N-glycans and many O-glycanes of glycoproteins as well as gangliosides.
By different modifications and binding types, the neuraminic acids contribute to the structural variety of glycoconjugates and have a great influence on numerous biological processes.
While sialinic acids play an important role in various biological processes, until recently, nothing was known about the importance of their N-acetyl or N-glycolyl side chain in these processes. The physiological precursor of all natural sialinic acids is N-acetylmannosamine. By the application of non-physiological N-acyl-mannosamines or glucosamines whose side chain is extended by one or more methylene groups, the corresponding neuraminic acids are biosynthesized (Grunholz et. al., 1981; Kayser et al. 1992).
A precursor such as N-propanoylmannosamine (ManNProp) is metabolized into N-propanoylneuraminates and subsequently, as N-propanoyineuraminic acid (NeuNProp), it is incorporated into the membrane proteins of the cells as well as into the serum glycoproteins (gangliosides) (Kayser et al., 1992).
Cell culture experiments have shown that biological processes such as viral infections and cell proliferation are permanently influenced by thus modified neuraminic acids.
DE 197 38 484 discloses the use of N-propanoylmannosamine, N-isopropanoyl-mannosamine and/or N-cyclopropanoylmannosamine (i.e., more correctly, N-cyclopropylcarbonylmannosamine) for the preparation of a medicament for myelinization and remyelinization. The capability of the above mentioned mannosamine derivatives of effecting myelinization and remyelinization is based on their property of being stimulators of oligodendrocytes.
Further, WO 00/07602 describes that particular N-acylmannosamines (such as N-acetyl-, N-propanoyl-, N-glycolyl-, N-formylmannosamine) are suitable for the modulation of neuronal growth or for the enhancement or inhibition of neurite growth. However, these compounds have the drawback that their effectiveness is rather low. On the other hand, WO 00/07602 also discloses O-acylated derivatives of the above mentioned compounds; in particular, N-glycolylmannosamine pentaacetate is mentioned. However, all the glycolylmannosamine derivatives have the drawback of being antigenic.
Surprisingly, it has been found that special N- and O-acylated mannosamine compounds can stimulate neurite growth significantly better as compared to the compounds of WO 00/07602. N-propanoyl- and N-cyclopropylcarbonyltetra-acetylmannosamine have proven particularly suitable (among the non-O-acylated compounds N-propanoylmannosamine has been found to be most effective.